Ion channel is an important membrane protein family in cell membrane. It plays an important role in the process of neuromuscular excitement, hormone secretion, cell differentiation, sensory conduction, learning and memory, blood pressure control, salt and water balance, etc. It has been found through studies that mutations of more than 60 kinds of ion channels are closely related to disease. At present, ion channel has become the third-largest drug target following GPCR (G protein coupled receptor) and protein kinase (Yu et al., Science's STKE, 2004, 253, 15-21). There are more than 400 kinds of genes encoding ion channels in human genome, wherein the potassium ion channel superfamily has the most members. Potassium ion channels can be classified into four main categories according to their functions and structural features: inward rectifier potassium channels (Kir), two pore potassium channel (K2p), calcium-activated potassium channel (KCa) and voltage-gated potassium channel (Kv) (H. Wulff et al., Nature Reviews Drug Discovery, 2009, 8(12), 982-1001). Potassium ion channels play an important role in the regulation of excitability of neurons. The ion mechanism thereof is that the intracellular concentration of potassium ion is higher than the extracellular concentration, positively charged potassium ions efflux after the depolarization of membrane potential activates the channel, and thus membrane potential becomes negative (negative polarization or hyperpolarization) and cell excitability is decreased. Recent studies on epileptic genetics have shown that abnormalities of potassium ion channel can directly lead to epilepsy (H. Wulff et al., Chemical Review, 2008, 108(5), 1744-1773), such as benign neonatal familial convulsions (BFNC).
The voltage-gated potassium channel (Kv) is an important member of the potassium channel superfamily, and includes 12 members, KV1.X to KV12.X. The KCNQ channel is the 7th member (Kv7) of the voltage-gated potassium channels, and includes 5 subtypes named KCNQ1 to KCNQ5, respectively. The locations and functions of different KCNQ subtypes are different, for example, KCNQ1 mainly locates in heart and cochlea, and its mutation is closely related to congenital long-qt syndrome and congenital deafness; KCNQ2, KCNQ3 and KCNQ5 mainly locate in brain and ganglia, and are closely related to neuronal excitability; and KCNQ4 mainly locates in cochlear and vestibular hair cells, and is closely related to audition (D. A. Brown, et al., British Journal of Pharmacology, 2009, 156, 1185-1195). Compared with other voltage-gated potassium channel members, KCNQ channel has a relatively low activation threshold, and can be opened at an action potential of −60 mV, and the activation of the KCNQ channel is relative slow, and the KCNQ channel does not loss the activity thereof even during a sustained depolarization. These features make the KCNQ channel at the fundamental level in regulating cell excitability, the opening of KCNQ channel can inhibit neural excitability, and the inhibition of the functions of KCNQ channel can lead to the depolarization of nervous cell membrane potential, and thus increasing excitability, and inducing more nerve impulses. Therefore, KCNQ channel is an important medical target for preventing and treating a variety of nerve excitatory disorders.
Based on the above features of KCNQ target, a KCNQ potassium channel agonist can be used for treating not only epilepsy, but also other disorders caused by excessive neural excitability, such as convulsion, neuropathic pain, acute ischemic stroke, and neurodegenerative diseases, by activating potassium channels and decreasing neural excitability (Dalby-Brown et al., Current Topics in Medicinal Chemistry, 2006, 6, 999-1023).
The reported KCNQ potassium channel agonists are as follows:
1. U.S. Pat. No. 5,384,330 discloses some compounds having the following structure,
which are characterized by a benzene ring substituted by ortho-diamino groups.
2. WO2005/087754 discloses a KCNQ potassium channel agonist having the following structure,
which is characterized by a benzene ring substituted by para-diamino groups, wherein one nitrogen is located in a saturated ring (or a heterocyclic ring when W is oxygen), and the adjacent positions of the other nitrogen are substituted by R1 and R2.
3. WO2008024398 describes the following structure,
which has a similar structure as that described in WO2005/087754, with a fused benzene ring structural unit on the N-heterocyclic hydrocarbon.
Up to date, the most representative KCNQ potassium channel agonist is retigabine (hereafter referred as RTG), an anti-epileptic drug developed by GSK (GlaxoSmithKline)) and marketed in 2011, with the following structure. RTG, which is the first systematic studied KCNQ potassium channel agonist, can activate KCNQ2-5 and is mainly used for treating adult patients suffering from partial seizure of epilepsy.
The structure of RTG contains an electron-rich benzene ring substituted by three amino groups, which results in that RTG is particularly easy to be oxidized and deteriorated during synthesis and storage. At the same time, there are many adverse reactions in clinical application, including dizziness, drowsiness, fatigue, confusion, tremor, poor coordination, diplopia, blurred vision, attention deficit, hypomnesis ataxia, aphasia, dysphonia, disequilibrium, increased appetite, hallucinations, myoclonus peripheral edema, hypokinesia, dry mouth, dysphagia, etc. Paruria is also a common toxic and side effect of RTG, including bladder swelling, thick-walled bladder, uroschesis, etc. On Apr. 26, 2013, the Drug Safety Commission of FDA announced that some of the color reactions were caused by RTG in the clinical application, including blue discoloration of the skin, retinal pigment abnormalities, etc. Given the specific mechanism of action is not clear, the patients receiving RTG is advised to take eye exam regularly (S. Jankovic et al., Expert Opinion on Drug Discovery, 2013, 8(11), 1-9; F. Rode et al., European Journal of Pharmacology, 2010, 638, 121-127).
WO2013060097, which is an early stage outcome made by the inventors of present invention and incorporated herein by reference in its entirety, discloses a KCNQ potassium channel agonist having the following structure:
wherein, when R1 is allyl or propargyl the compound not only retains the activity of activating the KCNQ potassium ion channel equal to or higher than that of RTG, but also exhibits a significant anti-epileptic action in vivo, with a protective effect comparable to that of RTG. Furthermore, preliminary pharmacokinetic study in mice demonstrated that the compound has a higher exposure amount in brain tissue than RTG. However, further safety assessment revealed that the compounds disclosed in WO2013060097 have a high neurotoxicity, for example, death of rats can be observed when the dose is greater than 30 mg/kg in the case of single oral administration of compound K21. The lethal dose is obviously higher than the reported lethal dose of RTG (100 mg/kg, according to data from FDA Pharmacology Review(s), Potiga tablets).